The effects of CRF and α-helical CRF on anxiety in normal and hypophysectomized rats

The effect of corticotrophin-releasing factor (CRF) on anxiety in normal and hypophysectomized (HYPOX) rats was investigated. Intracerebroventricular injection (i.c.v.) of 2 μg of CRF increased anxiety in the elevated plus maze test in normal and HYPOX rats. Anxiety was measured as the ratio of time spent in the open arms of the maze to total time spent in all arms of the maze. CRF also reduced head dipping and rearing in the hole board, and the number of entries into the arms of the plus maze. These latter changes in behavior were independent of the changes in anxiety. All behavioral effects of CRF in HYPOX rats were blocked completely by the CRF receptor blocker, α-helical CRF (50 μg). Completeness of hypophysectomy was assessed by measuring plasma corticosterone (CORT) level changes 20 min after i.c.v. CRF (2 μg). CORT levels of all HYPOX rats given CRF were well below (< 1/10th) resting baseline levels of normal rats. Moreover, i.c.v. injection of saline vehicle nearly tripled CORT levels over resting baseline in normal rats, and CRF increased CORT levels 2-fold over vehicle. Taken together, these findings replicate the observation that CRF administered i.c.v. to rats is selectively anxiogenic in the elevated plus maze. They also indicate that the anxiety produced by CRF does not involve activation of the pituitary-adrenal axis. Rather, CRF-induced anxiety depends on the binding of CRF to central nervous system CRF receptors. Finally, the plasma CORT data indicate that i.c.v. injection of saline vehicle is stressful, as is injection of CRF.     

CRF₂ mediates the increased noradrenergic activity in the hypothalamic paraventricular nucleus and the negative state of morphine withdrawal in rats

BACKGROUND AND PURPOSE

Recent evidence suggests that corticotropin-releasing factor (CRF) receptor signalling is involved in modulating the negative symptoms of opiate withdrawal. In this study, a series of experiments were performed to further characterize the role of CRF-type 2 receptor (CRF₂) signalling in opiate withdrawal-induced physical signs of dependence, hypothalamus-pituitary-adrenal (HPA) axis activation, enhanced noradrenaline (NA) turnover in the hypothalamic paraventricular nucleus (PVN) and tyrosine hydroxylase (TH) phosphorylation (activation), as well as CRF₂ expression in the nucleus of the solitary tract-A₂ noradrenergic cell group (NTS-A₂).

EXPERIMENTAL APPROACH

The contribution of CRF₂ signalling in opiate withdrawal was assessed by i.c.v. infusion of the selective CRF₂ antagonist, antisauvagine-30 (AS-30). Rats were implanted with two morphine (or placebo) pellets. Six days later, rats were pretreated with AS-30 or saline 10 min before naloxone and the physical signs of abstinence, the HPA axis activity, NA turnover, TH activation and CRF₂ expression were measured using immunoblotting, RIA, HPLC and immunohistochemistry.

KEY RESULTS

Rats pretreated with AS-30 showed decreased levels of somatic signs of naloxone-induced opiate withdrawal, but the corticosterone response was not modified. AS-30 attenuated the increased production of the NA metabolite, 3-methoxy-4-hydroxyphenylglycol, as well as the enhanced NA turnover observed in morphine-withdrawn rats. Finally, AS-30 antagonized the TH phosphorylation at Serine40 induced by morphine withdrawal.

CONCLUSIONS AND IMPLICATIONS

These results suggest that physical signs of opiate withdrawal, TH activation and stimulation of noradrenergic pathways innervating the PVN are modulated by CRF₂ signalling. Furthermore, they indicate a marginal role for the HPA axis in CRF₂-mediation of opiate withdrawal.     

Persistent anxiolytic affects after chronic administration of the CRF₁ receptor antagonist R121919 in rats

Corticotropin-releasing factor (CRF) functions as one of the major mediators of the mammalian stress response and appears to play a key role in the pathophysiology of mood and anxiety disorders. Small molecule CRF₁ receptor antagonists may represent a novel form of pharmacotherapy for these disorders. The therapeutic success of CRF₁ receptor antagonists will depend, in part, upon whether tolerance develops to the actions of these compounds and whether appropriate patterns of HPA axis function is maintained. This study evaluated the effects of long term (～4 week) treatment with the CRF₁ receptor antagonist R121919, on CRF receptor function, HPA axis activity, behavioral measures, adrenal gland size, and body weight gain.Animals treated with 20 mg/kg/day of R121919 spent significantly more time in the open field in a defensive withdrawal test (138 ± 36 s for R121919 vs 52 ± 12 s for vehicle, p = 0.01). No significant effect of chronic CRF₁ receptor blockade on basal ACTH or corticosterone concentrations were detected, nor were significant changes detected in an elevated plus maze test. Both vehicle- and R121919- treated rats showed increases in AUC and peak ACTH and corticosterone concentrations following air puff startle stress, without any overall group differences, although a clear but non-significant attenuation in HPA axis response was observable in R121919 treated animals. Chronic CRF₁ receptor blockade increased CRF peptide mRNA expression in the PVN and decreased CRF peptide mRNA expression in the central nucleus of the amygdala. Overall our results suggest that anxiolytic effects of chronic CRF₁ receptor antagonism persist following chronic administration without significant attenuation of the HPA axis’s ability to mount a stress response.This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’.     

CRF antagonist reverses the “anxiogenic” response to ethanol withdrawal in the rat

The role of the neuropeptide corticotropin-releasing factor (CRF) in mediating the behavioral effects of ethanol withdrawal in the rat was examined using the elevated plus-maze test. In Experiment 1, CRF (0.5 µg ICV) reduced the percentage of time spent on the open arms of the elevated plus-maze, consistent with an anxiogenic-like effect. CRF also reduced the total number of arm entries, indicating a reduction in general activity. Low doses (5 and 25 µg ICV) of the CRF antagonist, alpha-helical CRF produced no behavioral effects in the elevated plus-maze, while a higher dose (50 µg ICV) elicited CRF-like activity. In experiment 2, rats were maintained for 2–3 weeks on a liquid diet containing ethanol (8.5–11.5% v/v) or sucrose. Eight hours after withdrawal from the ethanol diet rats displayed anxiogenic-like responses as well as a reduction in general activity in the elevated plus-maze compared with rats withdrawn from control diet. Alpha-helical CRF significantly antagonized the anxiogenic-like effects of ethanol withdrawal in the plus-maze. General activity and physical signs of ethanol withdrawal such as tail stiffness, body tremor and ventromedial distal flexion were unaffected by alpha-helical CRF. Blood Alcohol Levels (BALs) determined immediately after removal of the ethanol diet showed no group differences in ethanol consumption. These results suggest that increased activity of central CRF systems may mediate the anxiogenic effects of ethanol withdrawal.     

Corticotropin-Releasing Factor (CRF)-Induced Disruption of Attention in Rats Is Blocked by the κ-Opioid Receptor Antagonist JDTic

Stress often disrupts behavior and can lead to psychiatric illness. Considerable evidence suggests that corticotropin-releasing factor (CRF) plays an important role in regulating the effects of stress. CRF administration produces stress-like effects in humans and laboratory animals, and CRF levels are elevated in individuals with stress-related illness. Recent work indicates that κ-opioid receptor (KOR) antagonists can block CRF effects, raising the possibility that at least some of the effects of stress are mediated via KORs. Here we examined the effects of CRF on performance in the 5-choice serial reaction time task (5CSRTT), a test used to quantify attention in rodents, as well as functional interactions between CRF and KORs. Male Sprague-Dawley rats were trained in the 5CSRTT and then each was implanted with an intracerebroventricular (ICV) cannula. After recovery and restabilization of performance, they received a single intraperitoneal (IP) injection of vehicle or JDTic (10 mg/kg), a KOR antagonist with long-lasting (>14 days) effects. In subsequent sessions, rats received ICV infusions of CRF (0.25–1.0 μg) or vehicle and were tested 60 min later. CRF dose-dependently disrupted performance as reflected by decreases in correct responding, increases in omission errors, increases in latencies to respond correctly, and increases in time to complete the session. JDTic attenuated each of these CRF-induced deficits while having no effects on its own. The persistent ability of JDTic to disrupt KOR function was confirmed using the tail immersion assay. These findings indicate that KOR antagonists can prevent acute stress-related effects that degrade performance in tasks requiring attention.     

Inhibition of the Formation of the Alzheimer's β-Amyloid Peptide

Anorexia and body weight loss are characteristic of many diseases, including cancer and AIDS. Neuropeptides play a pivotal role in the physiological mechanisms regulating food intake and body weight. Neuropeptide Y (NPY) is a key molecule of the orexigenic network for energy intake and for normal adaptive feeding response to energy deficits. Therefore, the NPY receptors (notably, Y1 and Y5) may be one of the most significant target classes for treatment of anorexia and body weight loss. In addition, several anorexigenic peptides including corticotropin-releasing factor (CRF), cholecystokinin (CCK), leptin and melanocortin (MC) are emerging as potential targets for anorexia. Antagonists for CRF 2 receptor, CCK A receptor, MC 4 receptor and leptin receptor may be useful in stimulating food intake. The development of highly specific and selective non-peptide antagonists for these receptors is awaited. Anorexia is a crucial and critical disease. Increasing knowledge of its pathophysiology could lead to innovative new medicines for anorexia-cachexia syndrome.     

Effects of the administration of miconazole by different routes on the biomarkers of the “steroidal module” of the Athlete Biological Passport

This article reports the results obtained from the investigation of the influence of miconazole administration on the physiological fluctuation of the markers of the steroid profile included in the “steroidal module” of the Athlete Biological Passport. Urines collected from male Caucasian subjects before, during, and after either systemic (i.e., oral and buccal) or topical (i.e., dermal) treatment with miconazole were analyzed according to validated procedures based on gas chromatography coupled to tandem mass spectrometry (GC–MS/MS) (to determine the markers of the steroid profile) or liquid chromatography coupled to MS/MS (LC–MS/MS) (to determine miconazole urinary levels). The results indicate that only after systemic administration, the markers of the steroid profile were significantly altered. After oral and buccal administration, we have registered (i) a significant increase of the 5α-androstane-3α,17β-diol/5β-androstane-3α,17β-diol ratio and (ii) a significant decrease of the concentration of androsterone, etiocholanolone, 5β-androstane-3α,17β-diol, and 5α-androstane-3α,17β-diol and of the androsterone/etiocholanolone, androsterone/testosterone, and 5α-androstane-3α,17β-diol/epitestosterone ratios. Limited effects were instead measured after dermal intake. Indeed, the levels of miconazole after systemic administration were in the range of 0.1–12.5 μg/ml, whereas after dermal administration were below the limit of quantification (50 ng/ml). Significant alteration started to be registered at concentrations of miconazole higher than 0.5 μg/ml. These findings were primarily explained by the ability of miconazole in altering the kinetic/efficacy of deglucuronidation of the endogenous steroids by the enzyme β-glucuronidase during the sample preparation process. The increase of both incubation time and amount of β-glucuronidase was demonstrated to be effective countermeasures in the presence of miconazole to reduce the risk of uncorrected interpretation of the results.     

Possible involvement of the opioid receptor gene expression in the mechanisms of the analgesic action of melatonin

In the present study, we attempt to analyse the potential involvement of the opioid receptor gene expression in the mechanisms of the analgesic action of melatonin. A trauma-pain model was established in Wistar rats by combining right - hind limb amputation with 50℃ tail - flick test. Antinociception was determined by tail-flick latency to hot waster at 50℃. Melatonin produced the antinociceptive effect in dose-dependent manner after i. p or i. c.v. administration Injected i. c. v. to rats, naloxone（10μg） obviously antagonized the antinociceptive effect induced by i.p. melatonin.     

延缓CRF进展的药物治疗

慢性肾功能衰竭(ohronic renalfailure,CRF)是多种原因引起的肾脏疾病的共同转归。CRF进行性恶化的机制尚未完全阐明,肾小球高灌注、高压力和高滤过的“三高”状态是促进CRF进展的重要机制。慢性肾功能衰竭的治疗在肾功能不全的不同时期,治疗的目的不同。在CRF发展至尿毒症期以前(GFR<10ml/min,Scr>707μmol/L)以药物治疗为主,治疗的目的是延缓肾功能衰竭的进程;当已经进展到尿毒症期时则需肾脏替代治疗,目的是维持和改善患者的生命。     

Proton pump inhibitors: the beginning of the end or the end of the beginning?

Despite the dramatic success of pharmacological acid suppression in healing peptic ulcers (PUs) and managing patients with gastro-esophageal reflux disease (GERD) a number of challenges remain in the management of acid-related disorders. Several new drugs are currently being investigated to provide a significant advance over current treatments. These include new drug formulations, novel proton pump inhibitors (PPIs) as well as potassium-competitive acid blockers (P-CABs), which have already reached clinical testing. Some others (like NO-releasing antisecretory compounds) are still in preclinical development and require proof of concept in humans. While H(2)-receptor antagonists (especially soluble or OTC formulations) will become the 'antacids of the third millennium' and will be particularly useful for on-demand symptom relief, clinicians will continue to rely on PPIs to control acid secretion in GERD and other acid-related diseases. Since an increasing proportion of patients fail to respond to the best PPI treatment, more potent and long-acting drugs and more effective regimens are needed.     

Hydrogen sulfide: from the smell of the past to the mediator of the future?

Gases such as nitric oxide and carbon monoxide play important roles both in normal physiology and in disease. In recent years, interest has been directed towards other naturally occurring gases, notably hydrogen sulfide (H₂S), which is both a potent vasodilator and a mediator of long-term potentiation in the brain. This article focuses on recent work that suggests a role for H₂S, and perhaps other gases, in the CNS and cardiovascular system.     

A review of the fate of inhaled α-quartz in the lungs of rats

The distribution of dust particles within the lungs and their excretion are highly associated with their pulmonary toxicity. Literature was reviewed to discern pulmonary translocation pathways for inhaled α-quartz compared to those for inhaled TiO₂. Accordingly, it was hypothesized α-quartz particles in the alveoli were phagocytized by alveolar macrophages but silica-containing macrophages remained in the alveoli for longer time in contrast to the rapid elimination from the alveoli seen for TiO₂-containing macrophages. In addition, it was presumed that free silica particles are translocated in the interstitium, possibly through the cytoplasm of Type I epithelial cells, as observed with TiO₂. Free silica particles are presumed to be phagocytized by interstitial macrophages soon after the particles penetrate the interstitium; these dust cells are then translocated to the ciliated airway regions in the lumen through bronchus-associated lymphoid tissue (BALT). The pulmonary retention half-time of dust particles in rats exposed to α-quartz is several times longer than that of rats exposed to TiO₂, as long as the lung dust burden is ≈ 3?mg. The reduced pulmonary particle clearance ability in rats exposed to α-quartz aerosol is presumably attributed to the long-term retention of dust cells both in the alveoli and in the interstitium; this retention may be caused by the reduced chemotactic abilities of α-quartz-containing dust cells. However, the accumulation of α-quartz-containing dust cells in the lungs is not associated with the occurrence of pulmonary inflammation.     

Blockade of γ-aminobutyric acid-receptors of the B-subtype inhibits the dopamine-induced enhancement of the release of cholecystokinin-like immunoreactivity from slices of rat dorsal caudatoputamen

Summary When slices of rat dorsal caudatoputamen (= neostriatum) are incubated in vitro, Choecystokinin-like immunoreactivity (CCK-LI) is released upon addition of veratridine (3.75 mol/l). This release is affected by dopamine and by -aminobutyric acid (GABA)-receptor agonists. Dopamine enhances the release by stimulating dopamine D₂-receptors and decreases it via D₁-receptors. GABA_A-receptor agonists enhance the veratridine-induced release of CCK-LI, while GABA_B-receptor agonists decrease it. In the present investigation, it was examined whether GABA-receptors are involved in the effect which dopamine exerts via D₂-receptors. The GABA_A-receptor antagonist bicuculline (10 mol/l)and the blocker of the GABA_A-receptor ionophore picrotoxin (1 mol/l) did not affect the dopamine (0.1 mol/1)-induced increase in the release of CCK-LI. However, the GABA_A-receptor agonist muscimol (1 mol/l) not only enhanced the release of CCK-LI, but also prevented a further enhancement by dopamine (0.1 mol/l). This effect of muscimol was blocked by bicuculline (10 mol/l). In the presence of -amino-n-valeric acid (0.1 mmol/l), which has been described to block GABA_B-receptors, dopamine no longer enhanced the veratridine-induced release of CCK-LI. -Amino-n-valeric acid also inhibited the pronounced enhancement of the release of CCK-LI caused by dopamine (0.1 mol/l) and 1 mol/l in the presence of the preferential D₁-receptor antagonist SCH 23390. The effect of -amino-n-valeric acid persisted in the presence of bicuculline (10 mol/l and 100 mol/l). (+)-Baclofen, a partial agonist at GABA_B-receptors, and the stereoisomer (–)-baclofen, a full agonist, also prevented the effect of dopamine on the veratridine-induced release of CCK-LI. The effects of both drugs may be due to desensitization of GABA_B-receptors, which has been described to develop quite rapidly. It is concluded that -amino-n-valeric acid blocks GABA_B-receptors and in this way prevents the enhancement of the veratridine-induced release of CCK-LI caused by dopamine via D₂-receptors. These data are interpreted as evidence that dopamine and GABA-neurons can directly or indirectly interact in the rat neostriatum. Send offprint requests to D. K. Meyer at the above address     

Effect of ECR on the Expression of Tau from the Brain of the Mice Induced by Overload Aluminum Salt

Aim: To study the effect of Ecdysterone (ECR) on the expression of Tau from the cerebral cortice and hippocampus and behaviors in passive avoidance reaction and spatial discrimination of the mice induced by overload aluminum salt.Methods Fourty-five NIH mice were randomly divided into five groups, the control group, the model group, the treated     

Effects of β-adrenoceptor antagonists on the firing rate of noradrenergic neurones in the locus coeruleus of the rat

Summary Acute i.v. administration of the non-selective -adrenoceptor antagonist dl-propranolol given in incremental doses (<40 mg/kg) did not affect the firing rate of locus coeruleus (LC) neurones in the rat, as revealed by single cell recording techniques. Furthermore, no effect was seen 4 h after a single i.p. dose of this -blocker (10 mg/kg). However, repeated treatment with dl-propranolol (1, 5, 10 or 20 mg/kg i.p., twice daily for 4 days) produced a significant, dose-dependent decrease of the average LC neuronal firing rate in comparison to controls. The dextro isomer of propranolol, which has negligible -blocking activity but the same local anaesthetic potency as the racemate, had no corresponding effect. The non-selective -adrenoceptor antagonist sotalol, which is one of the most hydrophilic -blockers, had much less inhibitory effect on LC neurones than dl-propranolol. The ₁-selective antagonist metoprolol did not change the firing of noradrenergic neurones in the LC after similar treatment for 4 days. However, when the rats were subjected to oral treatment for 28 days, metoprolol was found to produce a slight inhibitory effect although much less than dl-propranolol.In view of these findings we propose a stimulatory and mainly ₂-adrenoceptor-mediated control mechanism for the noradrencrgic neurones in the LC. This mechanism seems to be characterized by a delayed responsiveness.     

Evaluation of the cost-effectiveness of rifaximin-α for the management of patients with hepatic encephalopathy in the United Kingdom

Objective: Rifaximin-α 550?mg twice daily plus lactulose has demonstrated efficacy in reducing recurrence of episodes of overt hepatic encephalopathy (OHE) and the risk of hepatic encephalopathy (HE)-related hospitalizations compared with lactulose alone. This analysis estimated the cost effectiveness of rifaximin-α 550?mg twice daily plus lactulose versus lactulose alone in United Kingdom (UK) cirrhotic patients with OHE.

Method: A Markov model was built to estimate the incremental cost-effectiveness ratio (ICER). The perspective was that of the UK National Health Service (NHS). Clinical data was sourced from a randomized controlled trial (RCT) and an open-label maintenance study in cirrhotic patients in remission from recurrent episodes of OHE. Health-related utility was estimated indirectly from disease-specific quality of life RCT data. Resource use data describing the impact of rifaximin-α on hospital admissions and length of stay for cirrhotic patients with OHE was from four single-center UK audits. Costs (2012) were derived from published sources; costs and benefits were discounted at 3.5%. The base-case time horizon was 5 years.

Results: The average cost per patient was £22,971 in the rifaximin-α plus lactulose arm and £23,545 in the lactulose arm, a saving of £573. The corresponding values for benefit were 2.35 quality adjusted life years (QALYs) and 1.83 QALYs per person, a difference of 0.52 QALYs. This translated into a dominant base-case ICER. Key parameters that impacted the ICER included number of hospital admissions and length of stay.

Conclusion: Rifaximin-α 550?mg twice daily in patients with recurrent episodes of OHE was estimated to generate cost savings and improved clinical outcomes compared to standard care over 5 years.     

延缓CRF进展的药物冶疗

慢性肾功能衰竭(chronic renal failure,CRF)是多种原因引起的肾脏疾病的共同转归.CRF进行性恶化的机制尚未完全阐明,肾小球高灌注、高压力和高滤过的"三高"状态是促进CRF进展的重要机制.慢性肾功能衰竭的治疗在肾功能不全的不同时期,治疗的目的不同.